Creating Innovative Cell Therapies for Pediatric Cancer
The Orentas Lab is at the forefront of T-cell based adoptive immunotherapy. We created a highly active chimeric antigen receptor T-cell product against the CD22 antigen at the National Cancer Institute (NCI), and saw this discovery translated into clinical practice. This demonstrated this technology’s power to impact the lives of children suffering with pre B-cell leukemia.
CAR-T technology has allowed us to imagine multimerizing CAR T-cell specificities, such as a dual CD19 and CD20 CAR currently in clinical trials. This technology has also allowed us to test new ways to incorporate novel binder technologies that approach leukemia antigens in a novel way, such as a single-chain binder we developed with colleagues at the NCI for CD33, a target for acute myeloid leukemia. Our work in hematologic malignancies is focused on creating new and better tools, and new and better gene vectors to deliver CARs to the effector T cells that are active against disease.
Having seen dramatic success in adoptive immunotherapy for pediatric leukemia, our colleagues at the Ben Towne Center for Childhood Cancer and the CureWorks collaborative continue to develop high-throughput pathways and innovative multi-institutional trials to bring the latest developments to the bedside in order to quickly benefit as many children as possible, with the least amount of toxicity.
The morbidity and mortality that our children suffer due to pediatric solid tumors is unacceptable. Our group has therefore started developing new avenues to identify new therapeutic approaches for rhabdomyosarcoma, Ewing’s sarcoma, osteosarcoma and neuroblastoma. For some of these diseases, especially in the case of chemo-refractory or relapsed disease, little progress has been made in over 30 years. Our mission is to now bring the tools and insights we have learned from the adoptive immunotherapy of hematologic malignancies to bear on pediatric solid tumors.
- Schnieder D et al., 2018, A unique human immunoglobulin heavy chain variable domain-only CD33 CAR for the treatment of acute myeloid leukemia, Front Oncol, fonc.2018.00539
- Fry TJ et al., 2018, CD22-targeted T cells induce remission in B-ALL that is naïve or resistant to CD19-targeted CAR immunotherapy, Nat Med 24:20
- Walker AJ et al., 2017, Tumor antigen density and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase, Mol Ther 25:2189
- Schneider R et al., 2017 A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines, J Immunother Cancer 5:42
- Long AH et al., 2015, 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors, Nat Med 21:581
Applying CAR-T therapy to pediatric solid tumors
Our group has been using gene expression analysis tools to define new protein targets on the surface of pediatric tumors. Taking a broad approach to this challenge, we have defined a number of new targets by analyzing expression levels in the tumor of transcripts encoding cell surface proteins, and comparing them to normal tissues. By this approach we are constructing an accurate “surface-ome” i.e. a genomics-based definition of the receptors available for CAR-T targeting of the surface of pediatric solid tumors.
If pediatric solid tumors are fundamentally different from hematologic malignancies, and there are no single CAR-T targets than can prove therapeutically tractable, an accurate definition of the “surface-ome” allows us to design approaches that require multiple recognition steps before the anti-tumor T cell engages the tumor target in a specific manner. To that end, we have created an analytical pipeline that defines the two antigen targets most over-expressed together, that could form the basis for a CAR-T approach that requires both targets to be present for therapeutic efficacy.
- Orentas RJ et al., 2012, Identification of cell surface proteins as potential immunotherapy targets in 12 pediatric cancers, Front Oncol 2:194
- Orentas RJ et al, 2017, Paired expression analysis of tumor cell surface antigens, Front Oncol 7:173
Invading the tumor microenvironment
In addition to identifying new target antigens on the surface of pediatric solid tumors, we are now exploring ways to create better CAR-T cells that can evade the negative signals present in the tumor microenvironment. We have shown that differentiation agents or drugs that alter the epigenetic regulation of large classes of gene expression elements, such as retinoic acid, can impact the tumor microenvironment and reverse the negative signals that therapeutic T cells receive once they home to the tumor site. This is commonly referred to as “armoring” the CAR-T against the solid tumor microenvironment. In order to more rapidly advance our approaches to adoptive immunotherapy of solid tumors we have also been exploring the treatment of canine companion animals who also suffer from osteosarcoma. We believe developing therapy for canine osteosarcoma will benefit both patients and animals (i.e. “both ends of the leash”), and will serve as a means to rapidly advance and test our therapies.
We were one of the first groups to demonstrate that the T-cell receptor (TCR) from one T cell (for example a TCR specific for a tumor antigen) can be functionally expressed by means of a gene vector in a second T cell. That means that, much like CAR-T based therapies, a patient’s T cells can be expanded and then transduced with a second tumor-specific TCR. We have extensive experience in murine models of pediatric cancer, and will use them to demonstrate that a new generation of sarcoma-specific TCRs can be generated and can control disease. This approach is complementary to the CAR-T based approaches and the lessons learned with regard to evading local tumor-mediated immunosuppression will apply to both types of genetically engineered effector T cells.
- Long AH et al., 2016, Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas, Cancer Immunol Res 4:869
- Orentas RJ and Mackall CL, 2015, Emerging immunotherapies for cancer and their potential application in pediatric oncology, Crit Rev Oncol 20:315
- Meadors JL et al, Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy, Pediatr Blood Cancer 57:921
- Kohler ME et al., 2010 Early expression of stem cell-associated genes within the CD8 compartment after treatment with a tumor vaccine, Cell Immunol 265:65
See a complete list of Dr. Orentas’s publications on PubMed.
Rimas Orentas, PhD, is a principal investigator at the Ben Towne Center for Childhood Cancer Research, the director for scientific integration at CureWorks, part of the Immunology Integration Hub at Seattle Children's Research Institute and a professor in the Department of Pediatrics, University of Washington School of Medicine.